Dopamine (DA) neurotransmission plays key roles in learning, motivation and reward processes as well as working memory and cognition. Aberrations in presynaptic dopamine stores and release underlie several neuropsychiatric disorders including schizophrenia, ADHD, drug addiction and Parkinson's disease. The PI's laboratory in collaboration with the laboratory of Dr. David Sulzer recently introduced new optical probes termed "Fluorescent False Neurotransmitters" (FFNs) that were designed as tracers of dopamine to enable direct visualization of neurotransmitter uptake and release at individual synaptic terminals. FFNs provide the first means to optically image the neurotransmitter release in the brain and thus enable the examination of synaptic plasticity associated with pathogenesis and the action of therapeutics. New FFNs will be synthesized to optimize the key functional parameters of these probes, which include the selectivity of uptake, signal contrast, kinetics of evoked release, and photostability. Also, pH responsive FFNs will be developed. These aims will be achieved via systematic structural alterations of promising compound leads. PUBLIC HEALTH RELEVANCE: Dopamine neurotransmission plays key roles in many brain functions in both health (learning, reward processes, working memory and cognition) and disease (schizophrenia, drug addiction, Parkinson's disease). The new imaging agents developed in this application provide the first means to monitor dopamine function and malfunction on the level of individual synapses and as such will enable not only fundamental neuroscience but also CNS drug design and development.